Knee osteoarthritis with a high grade of Kellgren–Lawrence score is associated with a worse frailty status, KNHANES 2010–2013

Frailty as a syndrome of physical decline in late life is associated with adverse health outcomes. Knee osteoarthritis (KOA) could contribute to frailty conditions. The objective of this study was to evaluate the impact of KOA on frailty risk in a Korean National Health and Nutrition Examination Survey (KNHANES) cohort. In this study (N, total = 11,910, age; 64.10 years old [63.94–64.27; mean 95% CI], sex (female, %); 6,752 (56.69)), KOA patients were defined as those with knee joint pain and grade 2 Kellgren–Lawrence (K–L) or more on plain radiographic images who were 40 years old or older in Korean population data of KNHANES. The frailty index was calculated using 46 items related to co-morbidities and laboratory parameters. The impact of KOA on frailty risk was evaluated with logistic regression analyses. The prevalence of KOA patients was 35.6% [95% CI 34.7–36.46]. In polytomous logistic regression, the relative risk ratio (RRR) of KOA was significantly increased in the pre-frail group (2.76, 95% CI 2.30–3.31) and the frail group (7.28, 95% CI 5.90–8.98). RRR of frailty was significantly increased in patients with K–L grade 3 (1.36, 95% CI 1.13–1.63) and K-L grade 4 (2.19, 95% CI 1.72–2.79). Older age, higher BMI, smoking status, alcohol intake, low-income status, higher WBC count, higher platelet count, higher serum creatinine level and low estimated GFR were significantly associated with increased frailty risk. High hemoglobin and regular walking habits were associated with decreased frailty risk in KOA patients. In this large observation population- based survey cohort, KOA is linked to an increased risk of frailty syndrome. We found a significant connection between KOA and frailty syndrome. These results show that we need to think about the overall health of people with KOA and give them special care to prevent frailty syndrome.

Osteoarthritis (OA) is a common chronic degenerative joint disease, resulting in a diminished ability to adapt to external stressors [1][2][3] .These stressors could contribute to adverse outcomes including organ damage and mortality risk called frailty syndrome 4 .Frailty is defined as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes 3,5 .Frailty syndrome known as Fried's frailty phenotype is classically defined as the presence of at least 3 of 5 specific health deficits: unintentional weight loss, exhaustion, low physical activity, slow walking speed, and reduced grip strength 3 .Fried's frailty phenotype is classified into three categories based on the number of frailty indicators: robust (n = 0), prefrailty (n = 1 or 2), and frailty (n = 3) 3 .Any frailty indexes operationalize frailty by counting deficits; the more health deficits an individual has, the frailer they will be-i.e., the more susceptible to adverse health outcomes.The frailty index, calculated as a ratio of deficits present out of the total number of possible deficits, gives a continuous score from total fitness (0) to total frailty (1) 6,7 .

Frailty index
We developed the frailty index using a cumulative deficit model, including symptoms, signs, abnormal laboratory values, disease status, and disabilities according to the Rockwood clinical frailty scale 7 .Rockwood's frailty index was calculated as a ratio of deficits present out of the total number of possible deficits.The index gives a continuous score from total fitness (0) to total frailty (1).This means that the more deficits an individual has, the frailer they are.Our frailty index was constructed based on 46 items from the KNHANES data.These items included comorbidities, functional abilities, signs and symptoms, and laboratory values according to the Rockwood clinical frailty scale 6,7 .Comorbidities (46 items) included hypertension, pulse irregularity, myocardial infarction, angina pectoris, hypercholesterolemia, decreased high-density lipoprotein, hypertriglyceridemia, dyslipidemia, low vitamin D, diabetes, increased hemoglobin A1c, thyroid disease, dyspnea, bronchial asthma, chronic obstructive pulmonary disease, pulmonary tuberculosis, chronic hepatitis B, chronic hepatitis C, liver cirrhosis, renal failure, history of anemia, stroke, history of arthritis, limitation of motor function, chewing difficulty, weight loss, fatigue, the idea of suicide, decreased mobility, disability of self-care, disability of usual activities, pain/discomfort, anxiety/depressive mood, major depression, smoking status (those who had smoked 100 cigarettes or more in their whole life), current smoking (those who were currently smoking and had smoked 100 cigarettes or more in their whole life), stomach cancer, colon cancer, lung cancer, hepatic cell carcinoma, breast cancer, cervical cancer, and thyroid cancer.We classified subjects into robust (frailty index ≤ 0.10), pre-frail (0.10 < frailty index ≤ 0.21), and frail (frailty index > 0.21) groups 6,7 .

Statistical analysis
We analyzed the relative risk ratio (RRR; 95% CI) of frailty in control (n = 7670) and KOA subjects (n = 4240) (Fig. 1) by polytomous logistic regression.RRR was adjusted by age, sex, body mass index (BMI), smoking status, alcohol intake, low-income status, hemoglobin (Hb), hematocrit, white blood cell (WBC), platelet (PLT), blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (GFR).We analyzed clinical data in KOA subjects by analysis of covariance (ANCOVA) after adjusting for age, sex, and BMI.All statistical analyses were performed using Stata software V.16.0 (StataCorp, 4905 Lakeway Drive, College Station, Texas 77845 USA).Statistical significance was considered when the two-sided p-value was less than 0.05.The prevalence of KOA patients analyzed by estimated proportion (mean and 95% CI).

Study patients
From 44,085 subjects, 17,873 subjects aged ≥ 40 years were chosen.A total of 5,528 patients were excluded due to missing values.After excluding 435 patients with rheumatoid arthritis patients, 11,910 individuals were finally evaluated in this study (Fig. 1).The prevalence of KOA patients was 12.50% [95% CI 11.93-13.10].
Baseline characteristics of study subjects according to three frailty groups are summarized in Table 1.
Relative risk ratios of the frailty and pre-frail group compared to the robust group  2).

Discussion
In general, decreased BMI is a main feature of the frailty syndrome.This may lead to worsening nutritional status and a decrease in muscle mass, resulting in weight loss and muscle weakness, which are two common indicators of frailty syndrome.Increased BMI is related to the weight-bearing stress and an increased risk of knee osteoarthritis 15 .Our results revealed that increased RRR of BMI was associated with frailty in knee OA patients (Fig. 2), consistent with a previous study 16 .In our study, it can be observed that the frequency of normal weight group (Table 1) in the frailty group decreases compared to the robust and pre-frail groups, and that of the overweight group increases relatively.Also, overall distribution of the study subjects according to K-L grade, the frailty status and the BMI status show that the BMI is increased in the frailty group as the K-L grade increases.But that of the overweight group increases as the K-L grade increases (Supplement Fig. 1).These results could show the features of the survived frailty subjects in this study data.
Another previous study has reported that sarcopenic obesity is more closely associated with knee OA than nonsarcopenic obesity 13 .Sarcopenia may be the common denominator of knee OA and frailty syndrome.Sarcopenic obesity is more closely associated with knee OA than nonsarcopenic obesity, although both groups have equivalent body weights 17 .This finding supports the importance of the systemic metabolic effect of sarcopenia and sarcopenic obesity on knee OA 13,[16][17][18] .These results suggest that different pathogenesis in knee OA can contribute to the development of frailty syndrome.We cannot analyze the sarcopenia or the sarcopenic obesity by muscle mass or body composite because the data are not available of our analysis dataset.
Kanapuru et al. have reported that lower muscle mass might be a risk factor for knee pain in patients with radiographically mild knee OA, but not in those with radiographically severe OA 19 .In women, high fat mass and low lower extremity muscle mass are associated with the presence and severity of knee OA 20 .Lower extremity muscle mass is more closely correlated with knee OA than obesity in women 20 .
Our results showed leukocytosis and thrombocytosis in KOA were accompanied by the frailty syndrome (Table 2).Furthermore, we observed an increased risk of frailty syndrome related to leukocytosis in KOA (Fig. 2).Previous studies have also reported that leukocytosis, C-reactive protein, and IL-6 levels are associated with normal aging, sarcopenia, and late-life disease (such as cardiovascular diseases) 19 .Lohman et al. have reported the importance of obesity and increased dietary inflammatory index (DII) in frailty subjects 21,22 .It has been suggested that inflammatory pathways and disordered coagulation play a role in the pathology of frailty 19 .
We hypothesized that frailty might also drive OA development by creating an inflammatory environment to interfere with normal tissue health.Molecular and biochemical changes associated with OA might in turn promote frailty, resulting in an exorable deterioration of the joint.Therefore, frailty might be considered an additional risk factor for the development of OA.
Increased serum creatinine and decreased estimated GFR (CKD-EPI equation) reflect a decreased renal function in KOA patients with frailty syndrome (Table 2).Thus, the use of renal toxic agents such as nonsteroidal anti-inflammatory drugs (NSAID) should be cautious in these patients.
Our results revealed that the frequency of regular walking had negative correlations with frailty syndromes (Fig. 2).Our results suggest the need for a long-term, adequately powered, and randomized controlled trial of exercise interventions in knee OA patients for the treatment of frailty in the elderly.Such evidence will greatly support the future design of preventive strategies against disability in older persons.

Figure 1 .
Figure 1.Case selection flow chart of radiographic study subjects in the Korean National Health and Nutrition Examination Survey (January 2010-December 2013) (Missing values is defined as the data value that is not stored for a variable in the observation of interest).

Table 1 .
Baseline characteristics of total study subjects (adjusted by age, sex and body mass index).

Table 2 .
Clinical features in radiologic knee osteoarthritis (KOA) and control population according to frailty status (control; n = 10,374, KOA; n = 1536) (adjusted by age, sex, and BMI).SE standard error.
Figure 2. The relative risk ratio of demographic and clinical parameters in pre-frailty and frailty status compared to robust status in all radiologic study subjects (N = 11,910) in Korean National Health and Nutrition Examination Survey.BMI body mass index, Hb hemoglobin, Hct hematocrit, WBC white blood cell, PLT platelet, BUN blood urea nitrogen,eGFR estimated glomerular filtration rate.